Loss of vestibular hair cells can occur due to a variety of disorders and results in dysfunction of the vestibulo-occular reflex and loss of balance. Bilateral vestibular hypofunction due to aminoglycoside ototoxicity and other means is a devastating and currently untreatable chronic disorder because loss of vestibular hair cells is permanent. To date there is no prosthetic device such as a hearing aid or cochlear implant for loss of vestibular function. Complete recovery from vestibular loss may only be possible through replacement of the missing vestibular sensory cells and therefore it is important to investigate strategies for the restoration of vestibular sensory cells as potential treatment for these patients. During normal embryonic developmental the genesis of both auditory and vestibular hair cells depends on expression of the atonal homolog, math1. Recently we have demonstrated that delivery of the mathl gene can induce replacement of hair cells after aminoglycoside ototoxicity. Although a number of different vectors are capable of delivering genes to the inner ear, we have focused on the use of adenovectors because they induce transient gene expression, have well defined tropism that can be further modified, have a good safety record in clinical testing and are readily manufactured under GMP. In this phase I STTR we propose to translate our early research findings to more complete proof of feasibility of the product concept. Our objectives are to 1.) test if the mathl induced regeneration of sensory cells is due to transdifferentiation of cells in damaged sensory neuroepithelium, and 2.) determine if there is a relationship between the restoration of sensory cells and the delivered dose of vector expressing mathl. Phase II experiments will focus on the selection of an optimized vector design for formal preclinical testing. Our overall goal is to develop-a viable inner ear drug for balance disorders designed to treat bilateral vestibular hypofunction.